MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma.
MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma.
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DOI：
10.3389/fonc.2022.1058726
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
MYCN基因的扩增导致其在mRNA和蛋白质水平上的过表达。MYCN mRNA的过表达可能在促进神经母细胞瘤（NB）中发挥重要作用，而不仅仅是MYCN蛋白的翻译。在本研究中，我们报告了一种能够结合MYCN mRNA的3 'UTR并诱导MYCN mRNA降解的小分子化合物（MX25-1）;这导致了有效的细胞生长抑制和细胞死亡，特别是在MYCN扩增或MYCN 3' UTR过表达的NB细胞中。为了评估MYCN 3 'UTR介导的信号在促进MX 25 -1的抗癌活性中的作用，我们检查了肿瘤抑制microRNA（miRNA）let-7的状态和激活，其是MYCN扩增的NB中MYCN 3' UTR的靶标。我们首先观察到MYCN mRNA的过表达与let-7致癌靶点DICER 1、ARID 3B和HMGA 2的高水平表达相关。MYCN mRNA降解后，在MX 25 -1处理的细胞中，DICER 1、ARID 3B和HMGA 2的表达下调。let-7的抑制逆转了这些致癌mRNA的下调，并显著增加了NB细胞对MX 25 -1的抗性。我们的研究结果支持了由于基因扩增导致MYCN mRNA过表达在NB细胞生长和疾病进展中具有独立功能的观点，并表明靶向MYCN mRNA可能是治疗MYCN扩增NB的有吸引力的策略，既可以抑制MYCN的细胞存活作用，又可以激活let-7的肿瘤抑制作用。
Amplification of the MYCN gene leads to its overexpression at both the mRNA and protein levels. Overexpression of MYCN mRNA may also have an important role in promoting neuroblastoma (NB) beyond the translation of MYCN protein. In the present study, we report a small molecule compound (MX25-1) that was able to bind to the 3’UTR of MYCN mRNA and induce MYCN mRNA degradation; this resulted in potent cell-growth inhibition and cell death specifically in MYCN-amplified or MYCN 3’UTR overexpressing NB cells. To evaluate the role of MYCN 3’UTR-mediated signals in contributing to the anticancer activity of MX25-1, we examined the status and activation of the tumor suppressor microRNA (miRNA) let-7, which is a target of MYCN 3’UTR in MYCN-amplified NB. We first observed that overexpression of MYCN mRNA was associated with high-level expression of the let-7 oncogenic targets DICER1, ARID3B and HMGA2. Following MYCN mRNA degradation, the expression of DICER1, ARID3B and HMGA2 was downregulated in MX25-1-treated cells. Inhibition of let-7 reversed the downregulation of these oncogenic mRNAs and significantly increased resistance of NB cells to MX25-1. Our results from this study supported the notion that overexpression of MYCN mRNA due to gene amplification has an independent function in NB cell growth and disease progression and suggest that targeting MYCN mRNA may represent an attractive strategy for therapy of MYCN amplified NB, both by inhibiting MYCN’s cell-survival effects and activating the tumor-suppressor effect of let-7.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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